Poly(adenosinediphosphate-ribose)-polymerase or poly(ADP-ribose)-polymerase (PARP) exists in mammalian cells and most eukaryotic cells, and is a class of catalyzed polyglutase diphosphate ribosylated ribozyme. PARP is closely related to many physiological processes, including chromosomal stabilization, DNA damage identification and repair, gene transcription, and cell apoptosis and necrosis. After its discovery, the important role of PARP in DNA damage repair and maintenance of genome stability has attracted wide attention. In all types of DNA damage, DNA single-stranded lesions occur most frequently, and the enzyme involved in a series of repair pathways is PARP. PARP detects DNA breaks, and is activated after DNA damage and binds to DNA breaks through an N-terminal DBD (Dibenzamido Diphenyl Disulfide) containing two zinc fingers, increasing the catalytic activity by 10-500 times.
Conventional chemotherapy and radiotherapy directly or indirectly attack DNA, causing DNA damage to tumor cells and killing the cancer cells. In tumor cells, however, DNA repair enzyme is overexpressed, and DNA damage self-repair mechanism is activated, thereby generating chemotherapy and radiotherapy resistant. Research has shown that PARP inhibitor can block the DNA repair pathway, reducing the ability of tumor cells to repair itself, so the PARP inhibitor in combination with chemotherapy can effectively enhance the anti-tumor effect. Research also found that PARP inhibitor monotherapy effectively inhibits BRCA1/2 (breast cancer type susceptibility protein) gene deletion or mutation in breast cancer and ovarian cancer.
In summary, PARP inhibitor has broad application in antitumor research and therapy. Therefore, the present invention is intended on the basis of preliminary studies, to design and synthesize a new series of aza-phenalene-3-ketone derivatives. The activities of the derivatives have been screened and studies, and the derivatives can be used in anti-tumor drug research.